Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells

Jones, Juli E.; Esler, William P.; Patel, Rushi S.; Lanba, Adhiraj; Vera, Nicholas B.; Pfefferkorn, Jeffrey A.; Vernochet, Cécile

doi:10.1371/journal.pone.0169566

“…It has been reported that suppression of the DNL pathway is a potential target for inhibiting cancer cells , and thus, this study speculated that PMCTi might suppress the DNL pathway, which could lead to apoptosis induction in HepG2 cells. We investigated the inhibitory effect of 2.5 m m of the PMCTi for 24 h on the expression of ACLY, ACC, and FASN.…”

Section: Resultsmentioning

confidence: 89%

“…The new targeting of cancer therapies has focused on DNL enzymes to become one of the potential new chemotherapy drugs . Previous research has reported that the inhibition of ACC reduces tumor growth of pancreatic cancer xenografted in animal models and increases apoptosis in glioblastoma cell lines . Following small interfering RNA‐mediated inhibition of ACLY in MCF‐7 breast cancer cells, cell viability was suppressed and cell apoptosis was increased .…”

mentioning

confidence: 99%

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

Phokrai

¹

,

Poolsri

²

,

Suwankulanan

³

et al. 2018

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Suppression of the expression or activities of enzymes that are involved in the synthesis of de novo lipogenesis ( DNL ) in cancer cells triggers cell death via apoptosis. The plasma membrane citrate transporter ( PMCT ) is the initial step that translocates citrate from blood circulation into the cytoplasm for de novo long‐chain fatty acids synthesis. This study investigated the antitumor effect of the PMCT inhibitor ( PMCT i) in inducing apoptosis by inhibiting the DNL pathway in HepG2 cells. The present findings showed that PMCT i reduced cell viability and enhanced apoptosis through decreased intracellular citrate levels, which consequently caused inhibition of fatty acid and triacylglycerol productions. Thus, as a result of the reduction in fatty acid synthesis, the activity of carnitine palmitoyl transferase‐1 ( CPT ‐1) was suppressed. Decreased CPT ‐1 activity also facilitated the disruption of mitochondrial membrane potential (ΔΨm) leading to stimulation of apoptosis. Surprisingly, primary human hepatocytes were not affected by PMCT i. Increased caspase‐8 activity as a consequence of reduction in fatty acid synthesis was also found to cause disruption of ΔΨm. In addition, apoptosis induction by PMCT i was associated with an enhanced reactive oxygen species generation. Taken together, we suggest that inhibition of the DNL pathway following reduction in citrate levels is an important regulator of apoptosis in HepG2 cells via suppression of CPT ‐1 activity. Thus, targeting the DNL pathway mediating CPT ‐1 activity by PMCT i may be a selective potential anticancer therapy.

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“…ACACA (acetyl-CoA carboxylase or ACC1) catalyses the rate-limiting reaction in the biogenesis of long-chain fatty acids and is thus vital for cancer cell survival during hypoxia (Gao et al, 2016). Inhibition of ACACA can lead to either decreased cell proliferation (Jones et al, 2017;Singh, Yadav, Kumar, & Saini, 2015) or decreased apoptosis (Keenan et al, 2015) and increased risk of metastasis/tumor recurrence (in mice) (Rios Garcia et al, 2017). NR2C2 can inhibit cancer initiation, but promote cancer progression (Lin et al, 2017).…”

Section: F I G U R E 4 Autosomal Recessive Genes Analysismentioning

confidence: 99%

Exome sequencing in 51 early onset non‐familial CRC cases

Thutkawkorapin

¹

,

Lindblom

²

,

Tham

³

2019

Molec Gen & Gen Med

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Background Colorectal cancer ( CRC ) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi‐allelic autosomal recessive pathogenic variants. Methods The cohort was whole exome sequenced ( WES ) at 100× coverage. Both a dominant‐ and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young‐onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss‐of‐function) or allele frequency. Results We identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS 2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes ( BMPR 1A , BRIP 1 , and SRC ) , three truncating variants in possibly novel cancer genes ( CLSPN , SEC 24B , SSH 2 ) and four candidate missense variants in ACACA , NR 2C2 , INPP 4A, and DIDO 1 . We also identify five possible autosomal recessive candidate genes: ATP 10B , PKHD 1 , UGGT 2 , MYH 13 , TFF 3 . Conclusion Two clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.

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“…In addition, RAB6C‐AS1 is plausibly involved in the regulation of calcium channel and CoA carboxylase activity. Regulation of calcium channel activity is vital for the proper functioning of the nervous system (Kisilevsky & Zamponi, ) and dysregulation of CoA carboxylase is associated with some certain brain cancers including GBM (Jones et al, ). Furthermore, RAB6C‐AS1 has a notable prognostic value for patients with LGG, which shows the importance of this lncRNA in brain cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that some genes such as RASSF1 (Pelosi et al, 2010), SYK (Krisenko & Geahlen, 2015), iNOS (Vannini, Kashfi, & Nath, 2015), and NFAT transcription factor genes (Robbs, Cruz, Werneck, Mognol, & Viola, 2008) In addition, RAB6C-AS1 is plausibly involved in the regulation of calcium channel and CoA carboxylase activity. Regulation of calcium channel activity is vital for the proper functioning of the nervous system (Kisilevsky & Zamponi, 2008) and dysregulation of CoA carboxylase is associated with some certain brain cancers including GBM (Jones et al, 2017). Furthermore, RAB6C-AS1 has a notable prognostic value for patients with LGG, which shows the importance of this lncRNA in brain cancers.…”

Section: Discussionmentioning

confidence: 99%

Potential role of RAB6C‐AS1 long noncoding RNA in different cancers

Salavaty

¹

,

Motlagh

²

,

Barabadi

³

et al. 2018

Journal Cellular Physiology

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We found that RAB6C-AS1 lncRNA is mostly overexpressed in GC. Also, based on bioinformatic and systems biology analyses, RAB6C-AS1 might function either as an oncogenic factor or tumor suppressor in a tissue-specific manner. Thus, RAB6C-AS1 could be considered as a candidate biomarker for various malignancies, especially prostate and brain cancers. According to our results, RAB6C-AS1 has a notable prognostic value for patients with brain lower grade glioma.

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Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells

Cited by 81 publications

References 32 publications

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

Exome sequencing in 51 early onset non‐familial CRC cases

Potential role of RAB6C‐AS1 long noncoding RNA in different cancers

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